The Adjuvant Discovery Program supports the early stage discovery and initial characterization of novel adjuvant candidates for vaccines. The research must include (1) identification of novel adjuvant candidates through high throughput screening (HTS) approaches and validation that lead compounds stimulate human cells; (2) determination of the mechanism of action of select lead compounds, including the identification of the receptor(s) the adjuvant candidates work through and the cellular signaling pathways they activate; (3) optimization of lead adjuvant candidates through formulation and medicinal chemistry, guided by structure-activity relationship (SAR) studies; and (4) verification of the efficacy of lead compounds as vaccine adjuvants in vivo in an animal model. Projects must include animal model studies to test the adjuvant candidates with vaccines against: A) One or more NIAID Emerging and Re-emerging Infectious Disease Pathogens http://www.niaid.nih.gov/topics/emerging/pages/default.aspx), or B) One or more NIAID Emerging and Re-emerging Infectious Disease Pathogens as well as one or more other (non-HIV) pathogens relevant to human disease.